Design, Synthesis, and Biological Activity Studies of Istradefylline Derivatives Based on Adenine as A_2A Receptor Antagonists

Due to its double bond, istradefylline rapidly isomerizes to Z-istradefylline when exposed to normal daylight in dilute solution. To solve the poor photostability of the istradefylline solution, a series of istradefylline derivatives (in total 17 compounds, including II-1 and II-2 series) were designed and synthesized, and their biological activity in inhibiting cAMP was evaluated. The IC₅₀ values of compounds II-1-3, II-2-1, II-2-2, II-2-3, II-2-4, and II-2-6 were 7.71, 6.52, 6.16, 7.23, 7.96, and 9.68 μg/mL, respectively, which had the same order of activity as that of istradefylline (IC₅₀ value was 1.94 μg/mL). The preliminary structure–activity relationship suggested that the 6-amino in adenine played an important role in binding an A_2A receptor. The results of photostability experiments showed that the photostability of the target compounds of II-1 and II-2 series was improved when compared with that of istradefylline.